The rat has been of limited use for studying starvation in man because it survives for a short time and it does not conserve protein. Preliminary studies from this laboratory indicate that both of these difficulties can be obviated by using a rat made obese by feeding a high fat diet. We propose to evaluate systematically the obese rat as a model for studying starvation in man by comparing its metabolic and hormonal response to starvation to that previously described in man. Particular attention will be focused on the mechanisms by which the utilization of "fat" leads to protein conservation and the role of thyroid hormone in this adaptation. In addition, we will study the interaction of ketone body and glucose metabolism in brain. Obese rats and non-obese controls of comparable age will be studied during a 10-15 day fast at fixed intervals. We will determine changes in organ weights and composition, the concentrations of hormones, metabolites and amino acids in blood and the excretion of nitrogenous products and ketone bodies in urine. In addition, we will determine arteriovenous differences for glucose, ketone bodies, lactate and amino acids across muscle and brain. Use of an animal model will also enable us to determine simultaneously changes in key regulatory enzymes and metabolites in muscle, brain and other tissues. Protein catabolism in skeletal muscle will be assessed from the excretion of 3-methylhistidine in urine, as well as from measurements of arterio-venous differences for amino acids across the hindquarter of an intact rat, and from determinations of protein synthesis and proteolysis in the isolated perfused rat hindquarter. In addition to starvation, the effect of lipid administration in vivo and perfusion of the hindquarter with FFA and ketone bodies on protein metabolism will be studied. Finally, in the event that plasma measurements indicate an alteration in T4 conversion to T3 during starvation, we will study the interconversion of these substances in perfused liver and muscle and the effect of small doses of exogenous T3 on protein catabolism in the intact rat.